2-aryl-tetrahydropyran-3-amines



United States Patent 0 3,419,555 Z-ARYL-TETRAHYDROPYRAN-3-AMINES HerndonJenkins, Richmond, Va., assignor to A. H. Robins Company Incorporated,Richmond, Va., a

corporation of Virginia No Drawing. Filed Oct. 24, 1965, Ser. No.505,010 25 Claims. (Cl. 260-247.2)

The present invention relates to certain novel aryl-substitutedheterocyclic compounds, and is more particularly concerned withZ-aryItetrahydropyran-3-amines.

The invention is especially concerned with novel compounds having theformula:

T RI! wherein Ar is selected from the group consisting of phenyl,lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl,trifluoromethylphenyl, and naphthyl, wherein is selected from the groupconsisting of amino, N-loweralkylamino, N,N dilower alkylamino, Nphenylloweralkylamino, morpholinoethyl, N- (hydroxylower alkyl)- amino,N,N di (hydroxylower-alkyl) amino, N-lOWeralkyl-N-(hydroxylower alkyl)amino, and a saturated monocyclic heterocyclic radical having up to amaximum of twelve carbon atoms and having up to a maximum of two heteroatoms in the ring and selected from the group consisting of morpholino,N-oxazolidone, piperidino, pyrrolidino and piperazino radicals, andwherein R" is selected from the group consisting of hydrogen and loweralkyl, and acid addition and quaternary ammonium salts thereof.

The basic compounds of the invention may be converted to either acidaddition salts with pharmaceutically acceptable acids such ashydrochloric, fumaric acid, etc., or to quaternary salts with alkylhalides such as methyl bromide, etc.

The compounds falling within the general Formula I may exist in morethan one form due to the possibility of stereo-isomerism resulting fromat least two centers of asymmetry. It is also to be understood that theforegoing Formula I includes the possible racemates as well as theindividual optically active forms.

The 2-aryltetrahydropyran-3-amines of the invention are useful asvasopressors, CNS stimulants, antidepressants, appetite suppressants,and nasal decongestants. In addition, certain of the compounds have beenfound to cause sedation in mice.

It is accordingly an object of the present invention to provide new anduseful 2-aryltetrahydropyran-3-amines, compositions thereof, and methodsof making and using the same. Other objects of the invention will beapparent to one skilled in the art.

In the definition of symbols in the foregoing Formula I and where theyappear elsewhere throughout the specification and claims, the terms havethe following significance.

The term lower-alkyl as used herein includes straight and branched chainradicals of up to eight carbon atoms inclusive and is exemplified bysuch groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl,isoamyl, hexyl, heptyl, octyl, and the like. Lower alkoXy has theformula O1ower-alkyl. The term cycloalkyl as used herein includesprimarily cyclic alkyl radicals containing three up to nine carbon atomsinclusive and encompasses 3,419,555 Patented Dec. 31, 1968 such groupsas cyclopropyl, cyclobutyl, cyclohexyl, cyclo pentyl, methylcyclohexyl,propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl,dimethylcyclohexyl, cycloheptyl, and cyclooctyl. Included in the termphenylloweralkyl are groups such as benzyl, phenethyl, methylbenzyl,phenpropyl, and the like.

When halogen is referred to herein, preferably but not necessarily ahalogen of atomic weight in excess of nineteen but not greater thaneighty is employed. Of the halogens, chlorine is preferred.

Among the suitable amino radicals included within the symbol areprimary, secondary and tertiary amino radicals, such as unsubstitutedamino (NH lower-alkyl-amino; dilower-alkyl-amino; phenylamino;phenyllower-alkylamino; di(phenyllower-alkyl) amino;lower-cycloalkylamino; dilower-cycloalkylamino;(hydroxylowenalkyl)amino; di- (hydroxylower-alkyl)-amino;1ower-alkyl--(hydroxyloweralkyl)-amino; basic saturated monocyclicheterocyclic radicals having up to a maximum of twelve carbon atoms, asexemplified by piperidino; lower-alkyl-piperidino, e.g., 2-, 3-, or4-lower-alkyl-piperidino; or 2,4-, 2,6-, or3,5-dilower-alkyl-piperidino; lower-alkoxy-piperidino; pyrrolidino;lower-alkyl-pyrrolidino; lower-alkoxy-pyrrolidino; morpholino;lower-alkyl-morpholino; piperazino; loweralkyl-piperazino (e.g., C- or N-methyl-piperazino); N (lower-alkyl)-C-(lower-alkyl)-piperazino; N(hydroxylower-alkyl)-piperazino; N-lower-aliphatic acyloxy-loweralkyl)and especially N-(lower-alkanoyloxy-lower-alkyl)- piperazino [e.g.,N-(acetoxy-, isobutyroxy-, or octanoyloxyethyl or propyl)-piperazino];lower-alkoxy-piperazino; N lower alkoxy-lower-alkylpiperazino, e.g.,N'-ethoxyethylpiperazino; and lower-carbalkoxy-piperazino.

The compounds of Formula I may be converted to and are most convenientlyemployed in the form of non-toxic pharmaceutically acceptable acidaddition or quaternary ammonium salts. Such salts also have improvedwatersolubility. Although the non-toxic salts are preferred, any saltmay be prepared for use as a chemical intermediate, as in thepreparation of another but non-toxic acid addi tion salt. The free basiccompounds of Formula I may be conveniently converted to their quaternaryammonium or acid addition salts by reaction of the free base with theselected acid or acid ester, e.g., an alkyl, cycloalkyl, alkenyl,cycloalkenyl or aralkyl halide, sulfate or sulfonate, preferably in thepresence of an organic solvent inert to the reactants and reactionproducts under the conditions of the reaction. The acids which can beused to prepare the preferred non-toxic acid addition salts are thosewhich produce, when combined with the free bases, salts the anions ofwhich are relatively innocuous to the animal organism in therapeuticdoses of the salts, so that beneficial physiological properties inherentin the free bases are not vitiated by side-effects ascribable to theanions.

Appropriate acid addition salts are those derived from mineral acidssuch as hydrochloric acid, hydrobromic acid, hydriodic acid, nitricacid, sulfuric acid, and phosphoric acid; and organic acids such asacetic acid, citric acid, lactic acid, fumaric acid, and tartaric acid.The quaternary ammonium salts are obtained, e.g., by the addition ofalkyl, cycloalkyl, alkenyl, cycloalkenyl, or aralkyl esters of inorganicacids or organic sulfonic acids, to the free base form of the selectedtertiary amino compound. The alkyl, cycloalkyl, alkenyl, cycloalkenyl,or aralkyl esters so used include such compounds as methyl chloride,methyl 3 bromide, methyl iodide, ethyl bromide, propyl chloride, allylchloride, allyl bromide, dimethyl sulfate, methyl benzene-sulfonate,methyl p-toluene sulfonate, benzyl halides such as p-chlorobenzylchloride and p-nitrobenzyl chloride, and the like.

The acid addition salts are prepared either by dissolving the free basein an aqueous solution containing the ap propriate acid and isolatingthe salt by evaporating the solution, or by reacting the free base andthe selected acid in an organic solvent, in which case the saltordinarily separates directly or can be conventionally recovered byconcentration of the solution or the like. Conversely the free base maybe obtained conventionally by neutralizing the acid addition salt withan appropriate base such as ammonia, ammonium hydroxide, sodiumcarbonate or the like, extracting the liberated base with a suitablesolvent, illustratively ethyl acetate or benzene, drying the extract andevaporating to dryness or fractionally distilling, or in otherconventional manner.

General method for the preparation of 2-aryl-tetrahydropyran-3-amines A2-aryl-3-bromo (or chloro) tetrahydropyran (1 mole) is treated with anexcess of the appropriate primary or secondary amine or ammonia (2 tomoles; ca. 5 moles preferred) either without solvent or in a solventwhich dissolves the reactants but does not itself enter the reaction(e.g., lower alcohols such as 2-propanol, aromatics such as toluene,ethers such as ethylene glycol dimethyl ether or other suitablesolvents; 2-propanol being especially useful). The reaction mixture isheated from 5 to 100 hours at elevated temperatures usually in the rangeof 110 to 190 C. (24 hours at 150 C. being typical). The product formedin this reaction may be isolated in a manner suitable for organic bases.For example, the basic product may be taken up in acid, neutral materialseparated from it by extraction of the aqueous solution with an organicsolvent (e.g., ether, ethyl acetate or toluene) and the basic productliberated from the acid solution by making the solution strongly basic.The basic product thus liberated may be taken up in an organic solvent(e.g., ether, chlorofrom, ethyl acetate or toluene), dried over ananhydrous salt which will form a hydrate (e.g., sodium sulfate,potassium carbonate or calcium sulfate), concentrated and distilled invacuo. A salt may be formed by treatment of the basic product with theappropriate acid. The amines may be separated into optical isomersthrough separation of their diastereoisomeric salts formed withoptically active acids (e.g., d-tartaric, l-malic acids, etc.).

The 2-aryl tetrahydropyran-El-amines of the invention which are primaryor secondary amines may be further reacted to form novel compoundshaving desirable pharmacological properties. One such method for furtherreaction is acylation, of which the following is a suitable generaldescription. The compounds are anti-depressants and sedatives.

The 2-aryl-tetrahydropyran-3-amines which are primary or secondaryamines may be acylated by the following general method. The2-aryl-tetrahydropyran-3-amine (1 mole) in an unreactive solvent (e.g.,chloroform or tetrahydrofuran) is treated dropwise (e.g., over 0.5 hour)with the desired acylating agent (1 equivalent) (e.g., acetic anhydride,ethyl chloroforrnate, diphenylcarbamoyl chloride or phenyl isocyanate)and, in those cases where an acid is liberated (e.g., the first 3acylating agents listed) may be treated simultaneously with a base (1equivalent) (e.g., sodium hydroxide or pyridine). After addition iscomplete, the product may be isolated by methods used in the art. Forexample, a chloroform solution of the product can be washed with acid,base and water, dried and concentrated and the crude product purified byfractional distillation or crystallization,

The following preparations are given by Way of illustration only and arenot to be construed as limiting.

Preparation 1.3-bromo-2-phenyltetrahydropyran Bromine (430 g., 2.69moles) was added dropwise to a solution of dihydropyran (227 g., 2.69moles) in absolute ethyl ether (250 ml.) at about -20 C. with vigorousstirring. This solution was added slowly with stirring to a solution ofphenylmagnesium bromide (3.00 moles) in absolute ethyl ether (1 liter)at about 2025 C. The reaction mixture was refluxed for one hour afterthe addition was completed and cautiously mixed with water (1 liter).The water layer was discarded and the ether layer washed again withwater, dried over sodium sulfate, concentrated and distilled.3-bromo-2-phenyltetrahydropyran (448 g., 1.86 moles) was obtained in a69% yield based on dihydropyran; B.P. 143-148 C. at 22 mm. pressure. The3-br0mo-2-phenyltetrahydropyran crystallized on standing and wasrecrystallized from isooctane giving white crystals melting at 41.5-42.5C. Cf. [R. Paul, Bull. Soc. Chem. (5), 2, 311-322 (1935)] Preparation2.3-bromo-2- 3-methoxyphenyl) tetrahydropyran 3-bromo-2- 3-methoxyphenyltetrahydropyran was prepared from bromine, dihydropyran and3-methoxyphenylmagnesium bromide in the same manner as described inPreparation 1. After working up the reaction mixture in the usualmanner, there was obtained a yield of 59% of the theoretical amount of3-bromo-2-(3-methoxyphenyl) tetrahydropyran. The product boiled at116120 C. at 0.2 mm. pressure; n 1.5632.

Preparation 3.-3-bromo 2-( l-naphthyl)tetrahydropyran Bromine (58 g.,0.36 mole) was added dropwise to a solution of dihydropyran (30.6 g.,0.36 mole) in absolute ethyl ether ml.) at about -15 C. with vigorousstirring. This solution was added slowly with stirring to a solution ofl-naphthylmagnesium bromide [prepared from 1-br0m0naphthalene (100 g.,0.48 mole) and magnesium (12.2 g., 0.50 mole) in absolute ether (200ml.) at about 20-25 C.]. The reaction mixture was refluxed two hours andhydrolyzed with dilute hydrochloric acid. The ether layer was separated,washed with water, dried over sodium sulfate, concentrated anddistilled. 3-bromo- 2-(l-naphthyl)tetrahydropyran (73 g., 0.25 mole)boiling at to 169 C. at 0.15 mm. pressure was obtained in a 69% yieldbased on the dihydropyran.

Preparation 4.3 bromo 2 (3-trifluoromethylphenyl) tetrahydropyran3-trifluoromethylphenylmagnesium bromide was added to the productresulting from the addition of bromine to dihydropyran in the samemanner as described in Preparation 1 to give3-bromo-2-(3-trifiuoromethylphenyl)tetrahydropyran in 69% of theoreticalyield. The product boiled at 134139 C. at 22 mm. pressure; n 1.5011.

Preparation 5.3-bromo-2-p-tolyltetrahydropyran 3-bromo 2p-tolyltetrahydropyran was prepared in 44% of the theoretical yield inthe same manner as described in Preparation 1 for the synthesis of3-bromo-2- phenyltetrahydropyran except that ptolylmagnesium. bromidewas used in place of phenylmagnesium bromide. The3-bromo-2-p-tolyltetrahydropyran was distilled at 90-94 C. at 0.05 mm.pressure; n 1.5573.

Preparation 6..3-bromo-4-methyl-2-phenyltetrahydropyran Bromine (1 mole)was added dropwise to a solution of 4-methyl-2,3-dihydro-4H-pyran [W. E.Parham and H. E. Holmquist, JACS, 73, 913 (1951)] (1 mole) in absoluteether (250 cc.) at about 20 C. with vigorous stirring. The resultantsolution was added dropwise over 30 minutes to a stirred solution ofphenylmagnesium bromide (1.3 moles) in absolute ether (1.5 liters) at 2025 C. The reaction mixture was refluxed for one hour after the additionwas completed and was then cautiously decomposed with an excess ofdilute hydrochloric acid. The aqueous layer was discarded and the etherlayer was washed with water, dried over anhydrous sodium sulfate,concentrated and distilled in vacuo giving 3-brorno-4-methyl-2-phenyltetrahydropyran.

Where the foregoing preparations produce a compound having a methyl orother lower-alkyl group, it is to be understood that compoundscontaining other lower-alkyl groups of straight or branched nature andcontaining up to eight carbon atoms inclusive, such as methyl, ethyl,propyl, isopropyl, butyl, sec. butyl, t. butyl, amyl, isoamyl, hexyl,heptyl, and octyl, are prepared in the same manner by substitution inthe process of the appropriate difierent lower-alkyl starting material.Likewise, where chloro or other halogen atom is present, althoughchlorine is preferred, further halogen compounds including iodo, bromo,chloro, and fluoro compounds are prepared starting from the appropriatehalogenated starting material. Similarly, where methoxy or otherlower-alkoxy group is present, other lower-alkoxy groups containingvarious lower-alkyl groups having up to eight carbon atoms inclusive areprepared in the same manner from the appropriate different lower-alkoxystarting material. Moreover, when one diloWer-alkylamino group, such asthe dimethylamino group, is present in a compound, otherdilower-alkylamino compounds are prepared in the same manner startingonly with the selected dilferent dilower-alkylamino compound. In thesame manner, ortho and meta substituted compounds are produced insteadof the para by utilizing the selected ortho or meta substituted startingcompound, and vice versa. Similarly, other molecular changes are readilymade.

The following examples are given by way of illustration only and are notto be construed as limiting.

Example 1.2-phenyltetrahydropyran-3-amine bimaleate3-bromo-2-phenyltetrahydropyran (48.2 g., 0.20 mole) in sufiicient2-propanol (210 ml.) to make a solution was saturated with ammonia at0-10" C. and this mixture was stirred and heated for 48 hours in aclosed stainless steel autoclave at about 145 C. The contents of theautoclave were then concentrated at reduced pressure to a pasty mass andpartitioned between isopropyl ether and sufficient 2 N hydrochloric acidto produce a strongly acidic aqueous layer. The isopropyl ether layerwas discarded and the aqueous layer was made strongly basic with 50%aqueous sodium hydroxide. An oil separated and was taken up inchloroform, washed with water, dried over sodium sulfate, concentratedand distilled. 2-phenyltetrahydropyran-3-amine (17.4 g., 0.098 mole) wascollected, boiling at l35-141 C. at 25 mm. pressure; 11 1.5465. Theneutralization equivalent found was 179.3, compared with 177.2calculated. The yield was 49% of the theoretical. The base was treatedwith an equimolar quantity of maleic acid in ethanol to give acrystalline salt. Recrystallization from a mixture of absolute ethylalcohol and ethyl acetate gave 2-phenyltetrahydropyran- 3-aminebi-maleate as white crystals melting at 14015- 14l.5 C.

Analysis.Ca1c. for C14H19N05 C, H, Found: C, 61.77; H, 6.54.

Utilizing the method of Example 1, 3-bromo-2-(3-chlorophenyl)tetrahydropyran is reacted with ammonia to produce 2(3-chlorophenyl)tetrahydropyran-3-amine.

Example 2.2- 3-methoxyphenyl) tetrahydropyran-3- amine hydrochloride Thepreparation of 2-(3-methoxyphenyl)tetrahydropyran-3-arnine was carriedout in the same manner as given in Example 1 by the reaction of ammoniaand 3- bromo-2-(3rnethoxyphenyl)tetrahydropyran in 2-propanol solvent.The product, 2-(3-methoxyphenyl)tetrahydropyran-3-arnine was obtained in44% yield, boiling at 133-136 C. at 0.22 mm. pressure; 11 1.5513. The2-(3-methoxyphenyl)tetrahydropyran-B-amine was treated with an excess ofan ether solution of hydrogen chloride to give a crystallinehydrochloride salt. The 2-(3-rnethoxyphenyl)tetrahydropyran-3 aminehydrochloride thus obtained was recrystallized from a mixture of2-propanol and ligroin giving white crystals :melting at l83l84 C.

Analysis.--Calc. for C H ClNO C, 59.13; H, 7.44; N, 5.75. Found: C,59.14; H, 7.52; N, 5.66.

The corresponding 2-(3-hydroxyphenyl)tetrahydropyran-3-amine is preparedby splitting of the methoxy group to the hydroxy group with ethanolicHBr.

Example 3 .-N -methyl-2-( l-naphthyl) tetrahydropyran-3'aminehydrochloride 3-bromo-2-(l-naphthyl)tetrahydropyran (72.5 g., 0.25 mole)and methylamine (45 g., 1.45 moles) in sufficient 2-propanol to give atotal volume of 175 uml. Were heated at 140 to 145 C. for 24 hours in aclosed steel vessel. The cooled reaction mixture was then concentratedin vacuo and partitioned between isopropyl ether and dilute aqueoushydrochloric acid. The acid layer was made strongly basic with 50%aqueous sodium hydroxide and extracted with chloroform. The chloroformsolution was dried over sodium sulfate, concentrated and distilled. N-methyl-Z- l-naphthyl)tetrahydropyran-3-arnine (11.0 g., 0.046 mole, 18%of theory) was isolated; B.P. 121- 137" C. at 0.2 mm. pressure.

The base dissolved in ether was treated with an excess of etherealhydrogen chloride and the white crystalline product thus obtained wasrecrystallized from a mixture of ethyl alcohol and ethyl acetate. Thewhite crystals of Nmethyl-2-( 1-naphthyl)tetrahydropyran-3-aminehydrochloride melted with decomposition at 238 to 245 C.

Analysis.-Calc. for C H ClNO: C, 69.18; H, 7.26; N, 5.04. Found: C,69.18; H, 7.22; N, 4.97.

The same manner, the corresponding N-hydroxyethylamino compound isprepared by substituting N-hydroxyethylamine for the methylarnine of thepreceding example, as further indicated below:

N- (Z-hydroxyethyl -Z-phenyltetrahydropyran-3-amine Ethanolamine (121g., 2.0 moles) and 24.1 g. (0.1 mole) of3-brorno-2-phenyltetrahydropyran was heated 18 hours at 173 C. Theexcess ethanolamine was distilled from the reaction mixture and theresidual oil distilled to give 9.0 g. (40.7%) of product, B.P. 109-113C. at 0.1 mm. pressure. The maleate salt melted at 96.5 C.

Analysisr Calc. for C H NO C, 60.52; H, 6.87; N, 415. Found: C, 60.32;H, 6.79; N, 4.08.

Example 4.-N-methyl-2-phenyltetrahydropyran- 3-amine hydrochloride3-bromo-2-phenyltetrahydropyran (48 g., 0.20 mole) and methylamine (31g., 1.00 mole) in Z-propanol (200 ml.) were heated at C. for 18 hours ina closed steel vessel. The cooled reaction mixture was concentrated invacuo and then partitioned between isopropyl ether and dilute aqueoushydrochloric acid. The acid layer was made strongly alkaline with 50%aqueous sodium hydroxide and the separated oil was extracted intochloroform. The chloroform extract was dried over anhydrous sodiumsulfate, concentrated in vacuo and distilled. N-methyl-2-phenyltetrahydropyran- 3 amine (19 g., 0.10 mole, 50% oftheory) was isolated; B.P. 133134 C. at 22 mm. pressure; 12 1.5356. Thebase was dissolved in ether and treated with ethereal hydrogen chloride.Two recrystallizations from acetonitrile yielded white crystals ofN-methyl-Z-phenyltetrahydropyran-3-amine hydrochloride, melting at216.5218.5 C.

Analysis.--Calc. for C H ClNO: C, 63.28; H, 7.97; N, 6.15. Found: C,63.15; H, 7.78; N, 6.01.

Example 5.-N,N-dimethyl-Z-phenyltetrahydropyran- 3-arnine hydrochloride3-bromo-2-phenyltetrahydropyran (96 g., 0.40 mole) and dimethylamine (90g., 2.0 moles) in 2-propanol (150 ml.) were heated 25 hours at 125 C. ina closed steel vessel. The cooled reaction mixture was concentrated invacuo and partitioned between dilute aqueous hydrochloric acid andisopropyl ether. The acid layer was made strongly basic with 50% aqueoussodium hydroxide and the oil which separated was extracted intochloroform. The chloroform layer was dried over anhydrous sodiumsulfate, concentrated and distilled.N,N-dimethyl-2-phenyltetrahydropyran-3-amine (11.0 g., 0.054 mole, 13%of theory) was isolated; B.P. 146151 C. at 25 mm. pressure; n 1.5313.The equivalent weight by anhydrous perchloric acid titration gave 205.7;205.3 calculated. The base was treated with ethereal hydrogen chlorideto give N,N-dimethyl-2-phenyltetrahydropyran 3 amine hydrochloride aswhite crystals. Two recrystallizations from absolute ethanol gave whitecrystals, melting point 195- 196.5 C.

Analysis.-Calc. for C H ClNO: C, 64.58; H, 8.34; N, 5.79. Found: C,64.55; H, 8.36; N, 5.78.

In the same manner, the corresponding N,N-di(hydroxyethyl)amino andN-methyl N hydroxyethylamino compounds are prepared by substitutingN,N-di(hydroxyethyl)amine or N-methyl-N-hydroxyethylamine for thedimethylamine of the preceding example.

Example 6.N,N-dimethyl-2-phenyltetrahydropyran- 3-amineN-methyl-2-phenyltetrahydropyran-3-amine (19 g., 0.10 mole), formic acid(26 g. of 90% aqueous formic acid, 0.50 mole) and formaldehyde (22.5 g.of 40% aqueous solution, 0.30 mole) were heated at 80 C. for 17 hours.The solution was then cooled, concentrated in vacuo and partitionedbetween ether and dilute aqueous hydrochloric acid. The hydrochloricacid solution was made strongly basic and extracted with chloroform. Thechloroform extracts were dried over anhydrous sodium sulfate,concentrated and distilled. N,N-dimethyl-2-phenyltetrahydropyran-3-amine(19 g., 0.093 mole, 93% of theory) was isolated; B.P. 140143 C. at 22mm. pressure. The free base was identical with that prepared in Example5.

Example 7.N- 2-morpholinoethyl -2-phenyltetrahydropyran-3-aminedihydrochloride monohydrate 3-bromo-2-phenyltetrahydropyran (24 g., 0.10mole) and 4-(2-aminoethyl)-morpholine (65 g., 0.50 mole) were heatedtogether for 55 minutes at 200 C. without a solvent. The reactionmixture was partitioned between dilute aqueous sodium hydroxide solutionand isopropyl ether. The isopropyl ether solution was dried,concentrated and distilled givingN-(Z-morpholinoethyl)-2-phenyltetrahydropyran (12.0 g., 41% of theory)boiling at 145- 150 C. at 0.1 mm. pressure; n 1.5336. Equivalent weightby titration was 144 compared with a calculated equivalent weight of145. The base was dissolved in ether and treated with an excess ofethereal hydrogen chloride. The precipitated solid was recrystallizedtwice from 2- propanol giving white crystals of N-(2-morpholinoethyl)-Z-phenyltetrahydropyran-3-amine dihydrochloride monohydrate, melting at226 to 228.5 C.

Analysis.Calc. for C I-I Cl N O -H O: C, 53.54; H, 7.93; N, 7.34; H O,4.74. Found: C, 53.42; H, 8.04; N, 7.28; H O, 4.84.

Example 8.Additional amine compounds Utilizing the method of Examples 1through 7, 3- bromo-phenyltetrahydropyran or other starting materialfrom said examples is reacted with a suitable amine reactant to providethe corresponding compounds according to the invention wherein the groupis piperidino, 4-methylpiperidino, 3,5-diethylpiperidino,4-methoxypiperidin0, pyrrolidino, 3-methylpyrrolidino,3-methoxypyrrolidino, 3-methylmorpholino, 3-methoxymorpholino,piperazino, N -methylpiperazino, N -methyl-2-methylpiperazino,N-(hydroxyethyl)piperazino, N- acetoxyethyl) piperazino,3-methoxypiperazino, N-ethoxyethylpiperazino, and3-(carbethoxy)piperazino.

Example 9.N-methyl-2- 3-trifiuoromethylphenyl) tetrahydropyran-3-aminehydrochloride 3-bromo-2-(3 trifiuoromethylphenyl)tetrahydropyran (61 g.,0.20 mole) and methylamine (40 g., 1.3 moles) in 2-propanol (150 ml.)were heated 19 hours at 140 C. in a closed steel vessel. The reactionmixture was concentrated in vacuo and partitioned between dilute aqueoushydrochloric acid and isopropyl ether. The acid layer was made stronglybasic with aqueous sodium hydroxide and the separated oil was taken upin chloroform. The chloroform extract was dried over sodium sulfate,concentrated and distilled.N-methyl-2-(3-trifluoromethylphenyl)tetrahydropyran-3-amine (26 g., 50%of theory) was isolated boiling at 128 to 133 C. at 22 mm. pressure; n1.4853. The oil was dissolved in ether and treated with etherealhydrogen chloride to give a crystalline salt. Two recrystallizationsfrom a mixture of 2- propanol and isopropyl ether gaveN-methyl-2-(3-trifiuoromethylphenyl tetrahydropyran-3-aminehydrochloride as white crystals melting at 206 to 207 C.

Analysis.Calc. for C H ClF NO: C, 52.79; H, 5.80; N, 4.74. Found: C,53.01; H, 5.82; N, 4.91.

Example 10.N,N-dimethyl-2-phenyltetrahydropyran- 3-amine methobromideN,N-dimethyl-Z-phenyltetrahydropyran-3-amine (19 g., 0.093 mole) wasdissolved in methyl ethyl ketone ml.) and a solution of methyl bromide(29 g., 0.30 mole) in methyl ethyl ketone (100 ml.) was added whilemaintaining the temperature at 25 C. Crystals formed and were removed byfiltration after standing overnight at room temperature. Tworecrystallizations of the crystals from a mixture of ethyl acetate andethyl alcohol gave N,N-dimethyl 2 phenyltetrahydropyran-3-aminemethobromide (22 g., 79% of theory) as white crystals; M.P. 199200.5 C.

Analysis.Calc. for C H BrNO: C, 56.00; H, 7.39; N, 4.66. Found: C,56.08; H, 7.46; N, 4.80.

Example 11.3-rnorpholino-3 p -toly1tetrahydropyran3-bromo-2-p-tolytetrahydropyran (40 g., 0.16 mole) and morpholine (68g., 0.78 mole) were mixed and then refluxed for 5 hours. The excessmorpholine was distilled off in vacuo. The residue was partitionedbetween dilute aqueous hydrochloric acid and isopropyl ether. The acidlayer was made strongly basic with 50% aqueous sodium hydroxide and theoil which separated was taken up in chloroform. The chloroform layer wasdried over sodium sulfate and distilled. The material boiled at 117 toC. at 0.01 mm. pressure and crystallized in the receiver (7.0 g., 17% ofthe theoretical yield). Five recrystalli- 9 zations from isopropyl ethergave 3-morpholino-2-p-tolyltetrahydropyran, M.P. 88.5 to 90 C.

Analysis.-Calc. for C H NO C, 73.53; H, 8.87; N, 5.36. Found: C, 73.58;H, 9.08; N, 5.51.

Example 12.--N- 2-phenylethyl -2-phenyltetrahydropyran-B-aminehydrochloride A mixture of 3-bromo-2-phenyltetrahydr0pyran (27 g., 0.11mole) and phenethylamine (121 g., 1.0 mole) was refluxed 20 hours andthe excess phenethylamine distilled ofi in vacuo. The cooled solutionwas partitioned between dilute hydrochloric acid and isopropyl ether.The acid layer was made strongly basic with 50% aqueous sodium hydroxidesolution and extracted with chloroform. The chloroform solution wasdried over sodium sulfate, concentrated and distilled. The materialboiling at 140-147 C. at 0.2 mm. pressure (17 g., 54% of theory) wascollected and converted to the hydrochloride salt in the usual manner.Two recrystallizations from absolute ethanol gaveN-(Z-phenylethyl)-2-phenylt-etrahydropyran-3-amine hydrochloride meltingat 248.5- 250 C.

Analysis-Cale. for C H ClNO: C, 71.79; H, 7.61; N, 4.41. Found: C,71.61; H, 7.58; N, 4.31.

Example 13.N-isopropyl-2-phenyltetrahydropyran- 3-amine hydrochloride3-bromo-2-phenyltetrahydropyran (48.2 g., 0.2 mole) and isopropylamine(59 g., 1.0 mole) were placed in a sealed steel vessel and thetemperature raised to 140 C. After maintaining the temperature at thislevel for 17 hours, the reaction mixture was cooled. The reactor wasopened and the solution made strongly basic with dilute aqueous sodiumhydroxide. The organic material was extracted into isopropyl ether,dried over sodium sulfate and distilled. The distillate was dissolved indilute aqueous hydrochloric acid, extracted with ether and the acidlayer made basic with aqueous sodium hydroxide. The organic material wasextracted into ether, dried over sodium sulfate and distilled (14.1 g.,32% yield); B.P. 145-151 C. at 22 mm. pressure; r1 1.5151. Thehydrochloride salt prepared in the usual manner was recrystallized fromethyl acetate to give N-isopropyl-2phenyltetrahydropyran-3-aminehydrochloride; M.P. 246247.5 C.

Analysis.Ca1c. for C H CINO: C, 65.74; H, 8.67; N, 5.48. Found: C,65.84; H, 8.67; N, 5.71.

Example 14.-2-phenyltetrahydropyran-3-amine3-chloro-2-phenyltetrahydropyran [R. Paul, Compt.

rend. 218, 1124 (1944)] (30.0 g., 0.153 mole) in sulficient 2-propanol(60 ml.) to make a solution was treated with ammonia (26 g., 1.53 moles)at about -20 C. and this solution was heated and stirred for 72 hours at175 C. in a closed stainless steel vessel. The reaction mixture wasworked up in the same manner as described in Example 1 to giveZ-phenyltetrahydropyran-3-amine (9.5 g., 0.054 mole, 35% of theory).This material was shown to be identical with that obtained in Example 1.

Example 15.-4-methyl-2-phenyltetrahydropyran-3-amine A solution of3-bromo-4-methyl-Z- henyltetrahydropyran (0.5 mole) in 2-propanol (400ml.) was saturated with ammonia at to C. and the solution was stirredand heated 48 hours in a closed stainless steel vessel at 150-160 C. Thereaction mixture was cooled, concentrated in vacuo and partitionedbetween water and dilute hydrochloric acid. The aqueous layer was madestrongly basic with 50% aqueous sodium hydroxide and the oil whichseparated was extracted into ether. The ether solution was dried overanhydrous sodium sulfate, concentrated and distilled in vacuo giving4-metl1yl-2-phenyltetrahydropyrarr -3-amine.

The following examples illustrate useful derivatives of the2-aryltetrahydropyran-3-arnines of the invention, prepared by subsequentacylation, having the formula:

Wherein R is selected from the group consisting of hydrogen,lower-alkyl, phenyl, phenyllower-alkyl, lowercycloalkyl, andhydroxylower-alkyl,

Wherein Ar is selected from the group consisting of phenyl,lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl,trifluoromethylphenyl, and naphthyl,

Wherein R is selected from the group consisting of hydrogen andlower-alkyl, and

Wherein R is selected from the group consisting of lower-alkyl,lower-alkoxy phenyllower-alkyl, amino, N- lower-alkylamino,N,N-dilower-alkylamino, phenylamino, diphenylamino, lowercycloalkylamino, dilower cycloalkylamino, phenyllower-alkylamino, anddi(phenyllower-alkyl) amino.

Example 16.N-acetyl-2-phenyltetrahydropyran-3-amine2-phenyltetrahydropyran-3-amine (18 g., 0.10 mole) in isopropyl etherml.) was treated with acetic anhydride (20.4 g., 0.20 mole) andtriethylamine (10.1 g., 0.10 mole) for 10 minutes at 50 C. On cooling awhite precipitate formed which was recrystallized from a mixture of2-propanol and ligroin giving N-acetyl-Z-phenyltetrahydropyran-3-amine(13 g., 0.060 mole, 60% of theory) as white crystals; M.P. 11S.5117 C.

Analysis-Calc. for C H NO C, 71.13; H, 7.81: N, 6.39. Found: C, 71.23;H, 7.84; N, 6.28.

Example 17.-N-carbethoxy-Z-phenyltetrahydropyran-3- amine2-phenyltetrahydropyran-3-amine (10 g., 0.056 mole) and pyridine (4.7g., 0.06 mole) in chloroform (100 ml.) were treated dropwise during 25minutes with a solution of ethyl chloroformate (6.5 g., 0.06 mole) inchloroform (50 ml.) at 0 C. When addition of the chloroformate wascompleted, the reaction mixture was stirred 30 minutes at 25 C., washedwith water, dried over anhydrous sodium sulfate, concentrated anddistilled; B.P. 124127 C. at 0.3 mm. pressure. The product (10.0 g, 0.04mole) was obtained in a 74% yield and crystallized on standing Tworecrystallizations from ligroin gave white crystals ofN-carbethoxy-2-phenyltetrahyd-royran- 3-amine melting at 72.5 to 74 C.

Analysis.-Calc. for C H NO C, 67.44; H, 7.68 N, 5.62. Found: C, 67.49;H, 7.62; N, 5.46.

Example 18.-N-(N,N'-diphenylcarbamoyl)- phenyltetrahydropyran-3 -amir1e2-phenyltetrahydropyran-3-amine (17.7 g., 0.10 mole) in tetrahydrofuran100 ml.) was treated dropwise during twenty minutes withdiphenylcarbarnoyl chloride (23 g., 0.10 mole) in tetrahydrofuran (100ml.). During the last half of the addition of the diphenylcarbarnoylchloride, sodium hydroxide (4.0 g., 0.10 mole) in water (50 ml.) wasadded simultaneously. Ether (100 ml.) was then added and the ether layerseparated, dried over sodium sulfate and concentrated to give a whitecrystalline solid. Two recrystallizations from 2-propanol gave N-(N,N-diphenylcarbarnoyl) 2 phenyl-tetrahydropyran-3-amine (24 g., 50% oftheory) as white crystals melting at 148.5 C.

Analysis.Calc. for C H N O C, 77.38; H, 6.49; N, 7.52. Found: C, 77.12;H, 6.64; N, 7.35.

in dry benzene (100 ml.) at 10 C. was treated dropwise during 30 minuteswith phenylisocyanate (12 g., 0.10

mole) in dry benzene (100 ml.) while stirring and cooling. The reactionmixture was warmed to 30 C. for 30 minutes, and chilled and the productremoved by filtration. 2phenyl-N-(phenylcarbamoyl)tetrahydropyran-3-amine (27 g., 0.09 mole) wasobtained in 90% yield; M.P. 182.5-184" C. Two recrystallizations from2-propanol gave the pure product as white crystals melting at l83184 C.

Analysis.Calc. for C H N O C, 72.95; H, 6.80; N, 9.45. Found: C, 72.87;H, 6.91; N, 9.49.

Using the procedure described above, the following compounds areprepared from the selected starting materials.

(l) N-methyl-N-(benzylcarbamoyl) 2(p-methylphenyl)tetrahydropyran-3-amine (2) N-methyl-N-(ethylcarbamoyl)2 (p-hydroxyphenyl)tetrahydropyran-3-amine (3)N-benzyl-N-(diethylcarbamoyl) 2 (p-ethoxyphenyl) tetrahydropyran-3-amine(4) N-cyclohexyl-N-(phenacetyl) 2(p-chlorophenyl)tetrahydropyran-3-arnine (5)N-(Z-hydroxyethyl)-N-(cyclohexylcarbamoyl) 2- m-trifluoromethylphenyl)-tetrahydropyran-3 -amine (6) N-methyl-N-(dicyclohexylcarbamoyl) 2 (1-naphthyl)tetrahydropyran-3-amine (7) N-methyl-N-(dibenzylcarbamoyl) 4methyl-2- phenyltetrahydropyran-3-amine (8) N-carbamoyl 2phenyltetrahydropyran-3-amine.

Example .-N- 2-phenyl-3-tetrahydropyranyl oxa'zolidinone Fourteen grams(0.0634 mole) of N-(2-hydroxyethyl) 2-phenyltetrahydropyran3-amine andg. (0.25 mole) of diethyl carbonate and a small piece of sodium wasmixed with 500 ml. of toluene. The toluene was distilled off over a twohour period, reducing the toluene volume to approximately 70 ml. Themixture was quenched with ice and the basic materials extracted withdilute hydrochloric acid. The toluene solution was dried andconcentrated to an oil which crystallized spontaneously. The solid wasrecrystallized from ethyl acetate to give 7.3 g. (43.5%) of materialmelting at l30l3l.5 C.

Analysis.Calc. for C H NO C, 67.99; H, 6.93; N, 5.66. Found: C, 67.86;H, 6.87; N, 5.53.

Where the foregoing examples produce a compound having a methyl or otherlower-alkyl group, it is to be understood that compounds containingother lower-alkyl groups of straight or branched nature and containingup to eight carbon atoms inclusive, such as methyl, ethyl, propyl,isopropyl, butyl, sec. butyl, t. butyl, amyl, isoamyl, hexyl, heptyl,and octyl, are prepared in the same manner by substitution in theprocess of the appropriate different lower-alkyl starting material.Likewise, where chloro or other halogen atom is present, althoughchlorine is preferred, further halogen compounds including iodo, bromo,chloro, and fiuoro compounds, are prepared starting from the appropriatehalogenated starting material. Similarly, where methoxy or otherlower-alkoxy group is present, other lower-alkoxy groups containingvarious lower-alkyl groups having up to eight carbon atoms inclusive areprepared in the same manner from the appropriate different lower-alkoxystarting material. Moreover, when one dilower-alkylamino group, such asthe dimethylamino group, is present in a compound, otherdiloweralkylamino compounds are prepared in the same manner startingonly with the selected different dilower-alkylamino compound. In thesame manner, ortho and meta products are produced instead of the para byutilizing the selected ortho or meta substituted starting material, andvice versa. Similarly other molecular changes within the scope of theinvention are readily made.

Formulation and administration.Effective quantities of any of theforegoing pharmacologically active compounds may be administered to aliving animal body in any one of various ways, for example, orally as incapsules or tablets, parenterally in the form of sterile solutions orsuspensions, and in some cases intravenously in the form of sterilesolutions. The free basic amino compounds, While effective, arepreferably formulated and administered in the form of their non-toxicacid-addition or quaternary ammonium salts for purposes of convenienceof crystallization, increased solubility, and the like.

Although very small quantities of the active materials of the presentinvention, even as low as 0.1 milligram, are effective when minortherapy is involved or in cases of administration to subjects having arelatively low body weight, unit dosages are usually five milligrams orabove and preferably twenty-five, fifty or one-hundred milligrams oreven higher, depending of course upon the emergency of the situation andthe particular result, e.g., anorectic or sedative, desired. Five tofifty milligrams appears optimum per unit dose, while usual broaderranges appear to be one to milligrams per unit dose. The active agentsof the invention may be combined with other pharmacologically activeagents, or with buffers, antacids or the like, for administration andthe proportion of the active agent in the compositions may be variedwidely. It is only necessary that the active ingredient constitute aneffective amount, i.e., such that a suitable effective dosage will beobtained consistent with the dosage form employed. Obviously, severalunit dosage forms may be administered at about the same time. The exactindividual dosages as well as daily dosages in a particular case will ofcourse be determined according to established medical principles underthe direction of a physician or veterinarian. Results uponadministration of these novel materials have thus far proved extremelygratifying.

The formulations of Example 21 are representative for thepharmacologically active compounds of the invention, but have beenespecially designed to embody as active ingredientN-lower-alkyl-2-phenyltetrahydropyran- 3-amines, or theirhydrochlorides, hydrobromides, methiodides, or like pharmaceuticallyacceptable salts.

Example 2 l .-Formulations -(1) Capsules.-Capsules of 5 ing., 25 mg.,and 50 mg. of active ingredient per capsule are prepared. With thehigher amounts of active ingredient, reduction may be made in the amountof lactose.

Typical blend for encapsulation: Per capsule, mg.

Active ingredient, as salt 5.0 Lactose 296.7

Starch 129.0 Magnesium stearate 4.3

Total 435.0

Additional capsule formulations preferably contain a higher dosage ofactive ingredient and are as follows:

100 mg 250 mg. 500 mg. Ingredients per per per capsule capsule capsuleActive ingredient, as salt 100.0 250.0 500. O Lactose 231. 5 126. 5 31.1 Starch 99. 2 54. 2 13. 4 Magnesium stearate". 4. 3 4. 3 5. 5

Total 435. 0 435. 0 550. 0

Per tablet, mg.

( 1) Active ingredient 5.0 (2) Corn starch 13.6 (3) Corn starch (paste)3.4 (4) Lactose 79.2 (5) Dicalcium phosphate 68.0 (6) Calcium stearate0.9

Total 170.1

Uniformly blend 1, 2, 4 and 5. Prepare 3 as a 10 percent paste in water.Granulate the blend with starch paste and pass the wet mass through aneight mesh screen. The wet granulation is dried and sized through atwelve mesh screen. The dried granules are blended with the calciumstearate and compressed.

Additional tablet formulations preferably contain a higher dosage of theactive ingredient and are as follows:

A. 50 mg. tablet Ingredients: Per tablet, mg. Active ingredient, as salt50.0 Lactose 90.0 Milo starch 20.0 Corn starch 38.0 Calcium stearate 2.0

Total 200.0

Ingredients: Per tablet, mg. Active ingredient, as salt 100.0 Lactose190.0 Dicalcium phosphate 172.2 Starch 54.0 Milo starch 21.6 Calciumstearate 2.2

Total 540.0

Uniformly blend the active ingredient, lactose, dicalcium phosphate,starch and milo starch. This blend is granulated with water and the wetmass is passed through a number eight mesh screen. The wet granules aredried at 140-160 degrees Fahrenheit overnight. The dried granules arepassed through a number ten mesh screens. These dried granules areblended with the proper weight of calcium stearate and the lubricatedgranules are then converted into tablets on a suitable tablet press.

C. 250 mg. tablet Ingredients: Per tablet, mg. Active ingredient, assalt 250.0 Corn starch 56.0 Carbowax 6000 (polyethylene glycol of M.W.

approximately 6000) 25.0 Lactose 35.0 Magnesium stearate 4.0

Total 370.0

Uniformly blend the active ingredient, corn starch, Carbowax 6000,lactose, and one-half the weight of magnesium stearate required. Thisblend is then slugged on a suitable tablet press. These slugs aregranulated through a ten mesh screen on an oscillating granulator. Thesegranules are then blended with the remainder of the magnesium stearateand the lubricated granules are then converted into tablets on asuitable tablet press.

14 D. 500 mg. tablet Ingredients: Per tablet, mg. Active ingredient, assalt 500.0 Corn starch (wet) 86.4 Milo starch 32.4 Calcium stearate 3.2Corn starch (dry) 26.0

Total 648.0

Uniformly blend the active ingredient, corn starch and milo starch. Thisblend is wet granulated using water and the wet mass is passed through anumber eight mesh screen. These wet granules are dried overnight atdegrees Fahrenheit. The dried granules are passed through a number tenmesh screen. The dried granules and weighed amounts of corn starch andcal-cium stearate are uniformly blended and these lubricated granulesare compressed on a suitable tablet press.

(3) Injectable-2% sterile solution.

Per cc. Active ingredient mg 20 Preservative, e.g., chlorobutanolpercent wt./vol 0.5 Water for injection q.s.

Prepare solution, clarify by filtration, fill into vials, seal, andautoclave.

(4) The pharmacologically active compounds provided by the presentinvention may also be administered successfully by embodying aneffective quantity thereof in an injectable suspension for injectioninto an animal body, in oral powders, suspensions or syrups, and inother acceptable dosage forms.

Various modifications and equivalents will be apparent to one skilled inthe art and may be made in the compounds, compositions, methods, andprocedures of the present invention without departing from the spirit orscope thereof, and it is therefore to be understood that the inventionis to be limited only by the scope of the appended claims.

I claim:

1. An aryltetrahydropyranamine selected from the group consisting of (1)compounds of the formula:

T RI! wherein Ar is selected from the group consisting of phenyl,lower-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl,trifluoromethylphenyl, and naphthyl, wherein is selected from the groupconsisting of amino, N-loweralkylamino, N,N-dilower-alkylamino,N-phenylloweralkylamino, 2-morp holinoethyl, N (hydroxyloweralkyl)-amino, N,N di(hydroxylower alkyl) amino,N-lower-alkyl-N-(hydroxylower-alkyl)-amino,. and a saturated monocyclicheterocyclic radical having up to a maximum of twelve carbon atoms andhaving up to a maximum of two hetero atoms in the ring and selected fromthe group consisting of morpholino, N-oxazolidinone, piperidino,pyrrolidino, and piperazino, and wherein R" is selected from the groupconsisting of hydrogen and lower-alkyl, and (2) non-toxicpharmaceutically acceptable acid addition and quaternary ammonium saltsthereof. 2. 2-(lower-alkoxyphenyl)tetrahydropyran-S-amine. 3.Nlower-alkyl-2-phenyltetrahydropyran-3-amine. 4 N,N dilower alkyl2-phenyltetrahydropyran-3- amine.

5. 2-(lower-alkylphenyl)tetrahydropyran-3-amine.

6. Z-phenyl(lower-alkyltetra'hydropyran)-3-amine.

7. 2-phenyltetrahydropyran-3-amine bimaleate.

8. 2-(3-methoxyphenyl)tetrahydropyran 3 amine hydrochloride.

9. N-methyl-2-(l-naphthyl)tetrahydropyran-3 amine hydrochloride.

10. N-methyl-2-phenyltetrahydropyran 3 amine hydrochloride.

11. N,N-dimethyl-2-phenyltetrahydropyran 3 amine hydrochloride.

12. N,N-dimethyl-2-phenyltetrahydropyran-3-amine.

13. N-(Z-morpholinoethyD-Z phenyltetrahydropyran- 3-aminedihydrochloride monohydrate.

14. N-methyl-2-(3 trifluoromethylphenyl)tetrahydropyran-3-aminehydrochloride.

15. N,N-dimethyl-2-phenyltetrahydropyran 3 amine methobromide.

16. 3-morpholino-2-p-tolyltetrahydropyran.

17. N-(Z-phenylethyl) 2 phenyltetrahydropyran 3- amine hydrochloride.

18. N-isopropyl-Z-phenyltetrahydropyran-3-amine drochloride.

19. 4-methyl-2-phenyltetrahydropyran-3-amine.

20. A compound having the formula:

wherein R is selected from the group consisting of hydrogen,lower-alkyl, phcnylloWer-alkyl, lower-cycloalkyl, andhydroxylower-alkyl,

wherein Ar is selected from the group consisting of phenyl,loWer-alkylphenyl, hydroxyphenyl, lower-alkoxyphenyl, halophenyl,trifluoromethylphenyl, and naphthyl,

wherein R" is selected from the group consisting of hydrogen andlower-alkyl, and

wherein R is selected from the group consisting of lower-alkyl,lower-alkoxy, phenyllower-alkyl, amino, N-lower-alkylamino,N,N-dilower-alkylamino, phenylamino, diphenylamino, cycloalkylamino,dicycloalkylamino, phenyllower-alkylamino, anddi(phenylloweralkyl)amino. 21. N-acetyl-Z-phenyltctrahydropyran-3-amine.22. N-carbethoxy-Z-phenyltetrahydropyran-3-arnine. 23. N N',Ndiphenylcarbamoyl) 2 phenyltetrahydropyran-S-amine.

24. 2-phenyl-N-(phenylcarbamoyl)tetrahydropyran 3- amine.

25. N-(Z-phenyl-3-tetrahydropyranyl)-0Xazolidinone.

No references cited.

NICHOLAS S. RIZZO, Primary Examiner.

JOSE TOVAR, Assistant Examiner.

US. Cl. X.R.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,419,555 December 31, 196E Herndon Jenkins It is certified that errorappears in the above identified patent and that said Letters Patent arehereby corrected as shown below: Column 6, line 39, "The should read Inthe line 53, "N, 415.

should read N, 4. l5 Column 8, line 64, morpholino3-pshould readmorpholino-2p- .Column 9, line 51, "ll24" should read 122-4 Column 10,line 47 "standing" should read standing. line 48, "phenyltetrahydroyran"should read phenyltetrahydropyran line 53,"diphenylcarbamoyl)phenyltetra should read diphenylcarbamoyl-Z-phenyltetra Column 16, line 18, "N-N'" should read Nw(N' Signed andsealed this 10th day of March 1970.

(SEAL) Attest: Edward M. Fletcher, 11'. WILLIAM E. SCHUYLER, JR.

Commissioner of Patents Attesting Officer

1. AN ARYLTETRAHYDROPYRANAMINE SELECTED FROM THE GROUP CONSISTING OF (1)COMPOUNDS OF THE FORMULA: 13.N-(2-MORPHOLINOETHYL)-2-PHENYLTETRAHYDROPYRAN3-AMINE DIHYDROCHLORIDEMONOHYDRATE.
 20. A COMPOUND HAVING THE FORMULA: